Human immunodeficiency virus (HIV) infection/Acquired Immunodeficiency Syndrome (HIV/AIDS) is a disease affecting primarily cells of the human immune system caused by infection with HIV. Since its discovery in 1981, AIDS has caused nearly 30 million deaths (as of 2009) (“Global Report Fact Sheet”. UNAIDS. 2010) and as of 2010, approximately 34 million people were infected with HIV worldwide (UNAIDS 2011 pg. 1-10). HIV/AIDS is now considered to be a chronic disease, rather than a fatal disease in many parts of the world (Knoll et al., (2007) Int J Dermatol 46 (12): 1219-28. While the prognosis of the disease can vary from patient to patient, both a patient's CD4+ T cell count and viral load are useful for predicted outcomes. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype (UNAIDS, WHO (December 2007). “2007 AIDS epidemic update” (PDF)). After the diagnosis of AIDS, if treatment is not available, survival ranges between 6 and 19 months (Morgan et al., (2002) AIDS 16 (4):597-632; Zwahlen and Egger (2006), UNAIDS Obligation HQ/05/422204, archived from the original on Apr. 9, 2008). Highly active antiretroviral therapy (HAART) and appropriate prevention of opportunistic infections reduces the death rate by 80%, and raises the life expectancy for a newly diagnosed young adult to 20-50 years (Knoll et al., supra; Antiretroviral Therapy Cohort Collaboration (2008), Lancet 372 (9635): 293-9; Schackman et al., (2006), Med Care 44 (11): 990-997).
HAART options are combinations (or “cocktails”) consisting of at least three medications belonging to at least two types, or “classes,” of antiretroviral agents, which may include non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside analogue reverse transcriptase inhibitors (NRTIs), integrase inhibitors and entry inhibitors. Initially treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). Combinations of agents which include protease inhibitors (PI) are used if the above regime loses effectiveness.
The current standard of care (SOC) treatments for HIV are generally fixed dose combinations (FDCs), comprised of cross-class drugs provided as a single pill taken once daily. Such FDCs include ATRIPLA® (tenofovir disoproxil fumarate/emtricitabine/efavirenz: tenofovir/NRTI+emtricitabine/NRTI, with efavirenz (a non-nucleoside reverse transcriptase inhibitor (NNRTI) from Bristol Myers-Squibb), Gilead Sciences, Inc.), COMPLERA® (tenofovir disoproxil fumarate/emtricitabine/rilpivirine: tenofovir/NRTI+emtricitabine/NRTI, with rilpivirine (a NNRTI from Tibotec/Johnson & Johnson), Gilead Sciences, Inc.); STRIBILD/QUAD (tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat: tenofovir/NRTI+emtricitabine/NRTI, with cobicistat-boosted elvitegravir (integrase inhibitor from Japan Tobacco), Gilead Sciences, Inc.); and 572-TRII® (abcavir/NRTI+lamivudine/NRTI, with dolutegravir (integrase inhibitor from Pfizer/Shionogi), ViiV (GlaxoSmithKline, Pfizer, Shionogi).
Combination antiretroviral therapy has made HIV a chronic manageable disease but is not a cure. HIV DNA incorporated into the DNA of latent or inactive T-cells and remains until the cell is activated. Current regimens do not address virus sequestered in latent cells. Moreover, current FDCs and their individual components suffer from side effects and failures, including: central nervous system (CNS) side effects, kidney toxicity, resistance/transmitted resistance, and failure with higher viral loads.
Prior efforts to develop a therapeutic vaccine have met with failure, or results have been difficult to interpret, including efforts using a vaccinia virus based approach, efforts utilizing subunit vaccines (HIV gp160), a whole-killed HIV isolate vaccine, and naked DNA vaccines. Accordingly, there remains a need in the art for compositions and methods to provide a functional cure of HIV infection (i.e., containment of HIV replication and prevention of disease in the absence of ongoing treatment) or a sterilizing cure of HIV infection (i.e., complete elimination of the virus), or to further ameliorate the symptoms of HIV infection or its sequelae, and/or to further enable an infected individual to control the virus and remain healthy.